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Cooperation between JNK1 and JNK2 in activation of p53 apoptotic pathway

N V Oleinik1, N I Krupenko, S A Krupenko

  • 1Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA.

Oncogene
|May 26, 2007
PubMed

Insights

10-formyltetrahydrofolate dehydrogenase (FDH) suppresses cancer cell proliferation. FDH induces apoptosis by activating c-Jun N-terminal kinases (JNK1 and JNK2) to phosphorylate p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Signaling

Background:

  • 10-formyltetrahydrofolate dehydrogenase (FDH) is downregulated in tumors.
  • FDH elevation suppresses cancer cell proliferation and induces apoptosis.
  • FDH-induced apoptosis involves p53 phosphorylation at Ser6.

Purpose of the Study:

  • To elucidate the mechanism of FDH-induced p53 phosphorylation.
  • To identify the kinases responsible for p53 phosphorylation.
  • To investigate the role of c-Jun N-terminal kinases (JNK) in FDH-mediated apoptosis.

Main Methods:

  • FDH expression in cancer cells.
  • JNK inhibitor (SP600125) treatment.
  • JNK1/JNK2 knockdown using siRNA.
  • p53 phosphorylation analysis (Ser6).
  • Co-immunoprecipitation and pull-down assays.

Main Results:

  • FDH induces phosphorylation of both JNK1 and JNK2.
  • JNK inhibition or knockdown prevents p53 phosphorylation and apoptosis.
  • JNK1 knockdown abolishes FDH-induced JNK2 phosphorylation, but not vice versa.
  • JNK2 directly associates with p53.
  • JNK1 phosphorylates JNK2, which then phosphorylates p53 at Ser6.

Conclusions:

  • FDH-induced apoptosis is mediated by the JNK1/JNK2 pathway.
  • A novel signaling cascade involves JNK1 activating JNK2, which subsequently phosphorylates p53.
  • This pathway represents a potential therapeutic target for cancer treatment.

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